In this application, we propose to investigate how antigen specific CD4+ T cells mediate glomerular injury, the first key step leading to glomerulonephritis (GN).T cell mechanisms have emerged as potentially the most important mediators in GN. However, antigen specific T cells are largely unanalyzed in existing GN models. It is unknown whether and how antigen specific T cells mediate glomerular injury in GN. Guided by our experience in T cell mediated autoimmune disease we are investigating the roles of T cells specific to autoantigen Col4alpha3NC1, a critical component of glomerular basement membrane, in a rat GN model. We discovered: 1) a 13-mer T cell peptide of Col4alpha3NC1 induced fatal GN similar to human late stage cresentic GN; 2) Col4alpha3NC1 specific CD4+ T cells of TH-1 type transferred severe GN in the naive recipients; 3) transfer of the T cells induced influx of monocytes/T cells into renal cortex. Thus, antigen specific CD4+ T cells may directly mediate glomerular injury and cause GN. Our hypothetical mechanism of glomerular injury mediated by antigen specific CD4+ T cells is as follows: 1. CD4+ T cells specific to autoantigen Col4alpha3NC1 are activated through molecular mimicry by microbial antigens; 2. activated T cells recognize a subpopulation of MHC class II+ glomerular cells; 3. recognition triggers monocytes/T cells influx into glomeruli; glomerular inflammation is initiated and maintained. With our unique model based on Col4alpha3 specific CD4 T cells and the T cell epitope, we will test our hypotheses: 1) We will identify a mimicking T cell peptide from microbial antigens based on the characterization of the 13-mer T cell peptide; 2) We will investigate the antigen presenting capacity of the MHC class II+ glomerular cell subpopulation, which may serve as the target for CD4+ T cells; 3) We will investigate the roles of infiltrating monocytes and T cells in the initiation and maintenance of glomerular inflammation after T cell transfer.